The purpose of the current research has been to develop a series of complementary projects using a behavior genetics approach to investigate pharmacological and behavioral factors important in drug abuse. Genetic factors involved in the acute, chronic and reinforcing effects of opioids have been investigated. This effort provides data important for testing pharmacological mechanisms thought to be important in the drug effect. For example, large differences in the potency versus efficacy of morphine-induced analgesia were found to vary independently as a function of genotype. In vivo methods for determining agonist effective receptor reserve and agonist affinity indicate that these two variables may be responsible for genetic differences in potency and therapeutic efficacy, respectively. In addition, occupancy and stimulus response curves help to determine the relative importance of drug and tissue dependent variables in the receptor-stimulus-effect cascade. The results of these types of studies demonstrate genotype and the use of classic receptor theory to be mutually beneficial for investigating pharmacological constructs important in the behavioral effects of a drug. Genotype by environment interactions thought to be important in the complex behavioral effects of a drug have been investigated in tolerance, sensitization and self-administration paradigms. Genetic variations in extinction patterns during self-administration studies suggested possible differences in context specific drug effects. Environmental conditioning studies using opioids in our laboratory and cocaine in collaboration with Clinical Neuropharmacology demonstrate genotype to be an important factor in conditioned drug-like effects and may play a role in drug-seeking behavior. Additional genotype by environment studies with molecular and biochemical geneticists in the laboratory demonstrated an additive-dominance model of inheritance to opioid-induced analgesia with a strong environmental component related to aggression.